Figure 11-1 - uploaded by Barbara E Jones
Content may be subject to copyright.
Neural systems generating wakefulness. This schematic depiction of a lateral, sagittal section of the cat brain represents neuronal systems implicated in the generation and maintenance of wakefulness. Outlined areas represent the region in the brainstem (oral pontine and midbrain reticular formation) and caudal diencephalon (posterior hypothalamus, subthalamus, and ventral thalamus) and in the basal forebrain where large lesions are associated with a decrease or loss of cortical activation and behavioral activity indicative of wakefulness. Whereas lesions of the central midbrain tegmentum primarily affect cortical activation, lesions of the ventral midbrain tegmentum predominantly alter behavioral arousal. Points marked with 'W (waking) indicate regions where high-frequency electrical stimulation produces cortical activation and arousal, as well as where neurons manifest a higher rate of spontaneous activity during wakefulness than during slow wave sleep (including the medullary, oral pontine, and midbrain reticular formation; the midline and intralaminar thalamic nuclei; the subthalamus and posterior hypothalamus; and the basal forebrain). Diamond-shaped symbols represent the neurons of the reticular formation, and dotted lines indicate their major ascending 

Neural systems generating wakefulness. This schematic depiction of a lateral, sagittal section of the cat brain represents neuronal systems implicated in the generation and maintenance of wakefulness. Outlined areas represent the region in the brainstem (oral pontine and midbrain reticular formation) and caudal diencephalon (posterior hypothalamus, subthalamus, and ventral thalamus) and in the basal forebrain where large lesions are associated with a decrease or loss of cortical activation and behavioral activity indicative of wakefulness. Whereas lesions of the central midbrain tegmentum primarily affect cortical activation, lesions of the ventral midbrain tegmentum predominantly alter behavioral arousal. Points marked with 'W (waking) indicate regions where high-frequency electrical stimulation produces cortical activation and arousal, as well as where neurons manifest a higher rate of spontaneous activity during wakefulness than during slow wave sleep (including the medullary, oral pontine, and midbrain reticular formation; the midline and intralaminar thalamic nuclei; the subthalamus and posterior hypothalamus; and the basal forebrain). Diamond-shaped symbols represent the neurons of the reticular formation, and dotted lines indicate their major ascending 

Citations

... 47 There are hypotheses that EEG slowing is triggered by changing inhibitory projections to cortical regions. 14,48 In the rotenone-treated rats, power spectral analysis also revealed theta rhythm slowing and increased beta rhythm during REM sleep. In this model, reduction of Theta frequency occurred after just 1 week of treatment and prior to all other RBD or PD symptoms. ...
Article
Full-text available
Background: Clinical observations reveal that rapid eye movement (REM) sleep behavior disorder (RBD) often develops prior to alpha-synucleinopathies including Parkinson's disease (PD). However, a causal relationship between alpha-synucleinopathy and Parkinsonian neurodegeneration has not been delineated. Methods: Rats were chronically treated with rotenone and EEG and EMG signals were recorded for analysis of sleep behavior, assisted by video recording of body movements. C-fos expression and TUNEL staining were used to assess neuronal activation and apoptosis, respectively. Chemogenetic manipulation of brain stem nuclei was conducted to ameliorate RBD symptoms in rotenone-treated rats. Results: Rats chronically exposed to rotenone exhibited progressive RBD features, from EEG slowing to REM sleep motor behavior and NREM muscle activities. Temporally, these phenomena correlated well with progressive alpha-synuclein aggregation and neuronal apoptosis in the sublaterodorsal tegmental nucleus (SLD) and gigantocellular ventricular reticular nucleus in the brainstem. Chemogenetic activation of glutamatergic neurons in SLD alleviated RBD symptoms in the rotenone model. Conclusion: Taken together, these results are consistent with a progressive degeneration in the REM sleep promoting and atonia circuit in early Parkinsonism that underlies the emergence of RBD symptoms, and demonstrate that the rotenone model is useful for further studies into RBD and its relationship to PD.
... Excessive daytime sleepiness including intrinsic sleep disorders like narcolepsy can have detrimental consequences [1]. Activation of monoaminergic neurons produces robust changes across sleep-wake states, whereas orexin, which is expressed exclusively in the perifornical area, dorsomedial as well as lateral hypothalamus, plays an important role in sleep-wake states [2][3][4][5]. It has been recognized that dysfunction of the orexin system is critically linked to human narcolepsy [6][7][8][9]. ...
Article
Orexinergic neurons, which are closely associated with narcolepsy, regulate arousal and reward circuits through the activation of monoaminergic neurons. Psychostimulants as well as 5-HT-related compounds have potential in the treatment of human narcolepsy. Previous studies have demonstrated that orexin receptor antagonists as well as orexin deficiencies affect the pharmacological effects of psychostimulants. However, little information is available on the consequences of psychostimulant use under orexin deficiency. Therefore, the present study was designed to investigate the abuse liability of psychostimulants in orexin knockout (KO) mice. In the present study, conditioned place preferences induced by methamphetamine and methylphenidate were not altered in orexin KO mice. Interestingly, we found that MDMA induced a conditioned place preference in orexin KO mice, but not in wild type (WT) mice. In addition, MDMA produced methylphenidate/methamphetamine-like discriminative stimulus effects in orexin KO mice, but not WT mice. Increases in 5-HT and dopamine release in the nucleus accumbens induced by MDMA were not altered by knockout of orexin; the steady-state level of G protein activation was higher in the limbic forebrain of orexin KO mice. In substitution tests using a drug discrimination procedure, substitution of 5-HT1A receptor agonist for the discriminative stimulus effects of methylphenidate was enhanced in orexin KO mice. These findings indicate that the orexinergic system is involved the rewarding effects of psychostimulants. However, there is a risk of establishing rewarding effects of psychostimulants even under orexin deficiency. On the other hand, deficiencies in orexin may enhance the abuse liability of MDMA by changing a postsynaptic signal transduction accompanied by changes in discriminative stimulus effects themselves.
... Sleep has important homeostatic functions, and SD is a stressor that has consequences for the brain, as well as many-body systems. Whether SD is due to anxiety, depression, or a hectic lifestyle, there are consequences of chronic SD (CSD) that impairs brain functions and contribute to allostatic load throughout the body [26]. CSD in young healthy volunteers has been reported to increase appetite and energy expenditure, increase levels of pro-inflammatory cytokines, decrease parasympathetic and increase sympathetic tone, increase blood pressure, increase evening cortisol levels, as well as elevate insulin and blood glucose. ...
Article
Full-text available
Objective: The aim of the present study is to investigate the effect of paradoxical sleep deprivation (SD) on learning and memory impairment and anxiety-like behavior in female Wistar albino rats. Methods: Eight-arm radial maze, open-field test, and light and dark test were used to assess the animals learning and memory and anxiety-like behavior. Results: SD associated with weaker learning and memory and increased anxiety- and depressive-like behavior in animals. Conclusion: Animals were exposed to SD showed learning and memory impairment and also exhibited increased anxiety- and depressive-like behavior when compared to control animals.
... In parallel with studies of EEG features and neuron activity in the sleep-waking cycle, an important role in investigations of brain structures involved in the transition from waking to sleep is played by microelectrostimulation methods. Half a dozen small loci have been described in the brainstem, from the pons to the hypothalamus, stimulation of which induces the development of slow-wave sleep, rapid sleep, or waking [8][9][10]. Despite the diffi culty and ambiguity in interpreting the consequences of electrical stimulation, the anatomical pattern of the system of brain structures to some extent or other involved in controlling sleep started to take shape. ...
Article
Full-text available
Electrophysiological methods of studying the nervous system have opened up new opportunities in sleep research. The spike frequencies of neurons in the cerebral cortex during sleep not only do not decrease but can significantly exceed their mean activity level during waking. One hypothesis explaining the high activity of cortical neurons when sensory perception thresholds are elevated and conduction of signals from the external world and the body to the cerebral cortex is virtually blocked is the visceral theory of sleep, which suggests that during sleep the cerebral cortex starts to receive interoceptive afferentation from all the body’s visceral systems for analysis. This article reviews studies addressing the direct experimental verification of this theory.
... 7,25 However, unlike results from other studies in healthy adults 25 and patients with chronic back pain, 23 we did not observe associations between opioid use and reduced %REM sleep. Given that endogenous opioid receptors are activated during SWS, 11,31 it is possible that use of exogenous opioids was associated with selective disruption of this stage of sleep in our sample of patients with FMI. As SWS disruption has been associated with lower pain thresholds 13 and increased pain ratings, 20 our results suggest that opioid use should be carefully monitored and considered in the management of pain symptoms in fibromyalgia. ...
... It is possible that this disruption is observed in SWS because of the endogenous opioid networks known to be involved in this stage of sleep. 11,31 Conversely, in individuals with high pain intensity, increasing opioid dosage may have the intended effect, facilitating deep sleep. Changes in central pain processing may also explain our observed interactive effect of pain intensity and opioid dosage on %SWS. ...
Article
Full-text available
Opioid use and sleep disruption are prevalent in fibromyalgia. Yet, the effects of opioids on physiological sleep in fibromyalgia are unclear. This study assessed associations between opioid use/dosage and polysomnographically assessed sleep in patients with fibromyalgia and insomnia (FMI) and examined moderating effects of age and pain. Participants (N = 193, Mage = 51.7, SD = 11.8, range = 18-77) with FMI completed ambulatory polysomnography and 14 daily diaries. Multiple regression determined whether commonly prescribed oral opioid use or dosage (among users) independently predicted or interacted with age/pain intensity to predict sleep, controlling for sleep medication use and apnea hypopnea index. Opioid use predicted greater %stage 2 and lower %slow-wave sleep (%SWS). Opioid use interacted with age to predict greater sleep onset latency (SOL) in middle-aged/older adults. Among opioid users (n = 65, ∼3 years usage), opioid dose (measured in lowest recommended dosage) interacted with age to predict SOL and sleep efficiency; specifically, higher dosage predicted longer SOL and lower sleep efficiency for older, but not middle-aged/younger adults. Opioid dose interacted with pain to predict %SWS and arousal index. Specifically, higher dosage predicted reduced %SWS and higher arousal index for individuals with lower pain, increased %SWS for individuals with higher pain, and did not predict %SWS for patients with average pain. Opioid use/dosage did not predict wake after sleep onset, total sleep time, %stage 1 or %rapid eye movement sleep. Opioid use prompts changes in sleep architecture among individuals with FMI, increasing lighter sleep and reducing SWS. Sleep disruption is exacerbated at higher opioid doses in older adults and patients with low pain.
... These impairments likely participate in ASD individuals' difficulties in planning and decision-making, which also contribute to disrupting daily living activities, including such routine tasks as choosing appropriate clothing, making telephone calls, using public transport, managing finances, and so forth [14,22,108]. OFC participates in the regulation of anger, aggression, and sleep, and lesions and dysfunction of it are associated with poor regulation of these functions [241,[250][251][252][253][254][255][256]. These dysregulations likely contribute to the ASD features of elevated intensity and frequency of anger and aggression, and elevated rates of sleep difficulties [13,14,22,170,173]. ...
Article
Full-text available
Autism spectrum disorder (ASD) is a challenging neurodevelopmental disorder with symptoms in social, language, sensory, motor, cognitive, emotional, repetitive behavior, and self-sufficient living domains. The important research question examined is the elucidation of the pathogenic neurocircuitry that underlies ASD symptomatology in all its richness and heterogeneity. The presented model builds on earlier social brain research, and hypothesizes that four social brain regions largely drive ASD symptomatology: amygdala, orbitofrontal cortex (OFC), temporoparietal cortex (TPC), and insula. The amygdala’s contributions to ASD largely derive from its major involvement in fine-grained intangible knowledge representations and high-level guidance of gaze. In addition, disrupted brain regions can drive disturbance of strongly interconnected brain regions to produce further symptoms. These and related effects are proposed to underlie abnormalities of the visual cortex, inferior frontal gyrus (IFG), caudate nucleus, and hippocampus as well as associated symptoms. The model is supported by neuroimaging, neuropsychological, neuroanatomical, cellular, physiological, and behavioral evidence. Collectively, the model proposes a novel, parsimonious, and empirically testable account of the pathogenic neurocircuitry of ASD, an extensive account of its symptomatology, a novel physiological biomarker with potential for earlier diagnosis, and novel experiments to further elucidate the mechanisms of brain abnormalities and symptomatology in ASD.
... In parallel with studies of EEG features and neuron activity in the sleep-waking cycle, an important role in investigations of brain structures involved in the transition from waking to sleep is played by microelectrostimulation methods. Half a dozen small loci have been described in the brainstem, from the pons to the hypothalamus, stimulation of which induces the development of slow-wave sleep, rapid sleep, or waking [8][9][10]. Despite the diffi culty and ambiguity in interpreting the consequences of electrical stimulation, the anatomical pattern of the system of brain structures to some extent or other involved in controlling sleep started to take shape. ...
Article
Full-text available
We present a historical review of the concepts of Russian researchers regarding the mechanisms and functional roles of sleep – I. P. Pavlov and his predecessors (I. R. Tarkhanov and M. M. Manaseina) and students (N. A. Rozhanskii and K. M. Bykov). This analysis leads to the conclusion that sleep is linked with the realization of functional operations not previously associated with sleep and not addressed by current neuroscience. Thus, a real understanding of sleep functions can be expected to come only with a new neurophysiological paradigm.
... Fortunately, this paradox can be resolved upon consideration of the complex and multifaceted interactions BP and the other antidepressants have with the brain. Importantly, DA and NE stimulate arousal (Jones 2005a;Jones 2005b;Osaka and Matsumura 1995), which is consistent with the fact that all four drugs increase both monoamines' neurotransmissions and would in this way increase rates of insomnia. Furthermore, although acetylcholine has been shown to inhibit MT synthesis, it also promotes rapid eye movement (REM) sleep (Jones 2005a;Jones 2004;Gillin and Sitaram 1984). ...
Article
Full-text available
Despite decades of clinical use and research, the mechanism of action (MOA) of antidepressant medications remains poorly understood. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly prescribed antidepressants—atypical antidepressants such as bupropion have also proven effective, while exhibiting a divergent clinical phenotype. The difference in phenotypic profiles presumably lies in the differences among the MOAs of SSRIs/SNRIs and bupropion. We integrated the ensemble of bupropion’s affinities for all its receptors with the expression levels of those targets in nervous system tissues. This “combined target tissue” profile of bupropion was compared to those of duloxetine, fluoxetine, and venlafaxine to isolate the unique target tissue effects of bupropion. Our results suggest that the three monoamines—serotonin, norepinephrine, and dopamine—all contribute to the common antidepressant effects of SSRIs, SNRIs, and bupropion. At the same time, bupropion is unique in its action on 5-HT3AR in the dorsal root ganglion and nicotinic acetylcholine receptors in the pineal gland. These unique tissue-specific activities may explain unique therapeutic effects of bupropion, such as pain management and smoking cessation, and, given melatonin’s association with nicotinic acetylcholine receptors and depression, highlight the underappreciated role of the melatonergic system in bupropion’s MOA. Electronic supplementary material The online version of this article (10.1007/s00213-018-4958-9) contains supplementary material, which is available to authorized users.
... Monoaminergic systems [serotonin (5-HT), norepinephrine (NE) and dopamine (DA)] play a well-recognized role in a variety of physiologic functions, including sleep-wake regulation (Jouvet, 1972;Steriade and McCarley, 1990;Jones, 2000;Siegel, 2000;Wisor et al., 2001). ...
Article
Full-text available
Excessive sleepiness (ES) is associated with several sleep disorders, including narcolepsy and obstructive sleep apnea (OSA). A role for monoaminergic systems in treating these conditions is highlighted by the clinical use of United States Food and Drug Administration-approved drugs that act on these systems, such as dextroamphetamine, methylphenidate, modafinil, and armodafinil. Solriamfetol (JZP-110) is a wake-promoting agent that is currently being evaluated to treat ES in patients with narcolepsy or OSA. Clinical and preclinical data suggest that the wake-promoting effects of solriamfetol differ from medications such as modafinil and amphetamine. The goal of the current studies was to characterize the mechanism of action of solriamfetol at monoamine transporters using in vitro and in vivo assays. Results indicate that solriamfetol has dual reuptake activity at dopamine (DA; IC50=2.9 μM) and norepinephrine (NE; IC50=4.4 μM) transporters, and this activity is associated in vivo with increased extracellular concentration of DA and NE levels as measured by microdialysis. Solriamfetol has negligible functional activity at the serotonin transporter (IC50>100 μM). Moreover, the wake-promoting effects of solriamfetol are likely due to activity at DA and NE transporters rather than other neurotransmitter systems, such as histamine or orexin. The dual activity of solriamfetol at DA and NE transporters and the lack of significant monoamine-releasing properties of solriamfetol might explain the differences in the in vivo effects of solriamfetol compared with modafinil or amphetamine. Taken together, these data suggest that solriamfetol may offer an important advancement in the treatment of ES in patients with narcolepsy or OSA.
... These include abrupt loss of consciousness and associated electroencephalogram (EEG) changes indicative of underlying brain electrical activity changes, muscle relaxation, reduced responsiveness to external sensory stimuli and modest metabolic, cardiovascular and respiratory changes. In adults, EEG changes in sleep typically show a 45-90 min cycle of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep repeating 4-6 times over the full sleep period (see Fig. 1) [47]. During wake and REM sleep, the EEG displays low voltage, faster and more mixed frequency activity than slower larger voltage fluctuations in NREM sleep. ...
... Nuclei in the reticular activating system (RAS) of the brainstem regulate consciousness, and thus transitions from wakefulness to sleep, and vice versa [47]. This system plays a key role in gating sensory information processing to preserve sleep in response to non-threatening stimuli or to elicit physiological activation responses to stimuli that may require more complex behavioural responses and rapid reawakening. ...
Article
Full-text available
Adequate sleep is important for good health and well-being, and inadequate sleep leads to impaired attention and performance. Persistent poor sleep is also associated with cognitive and metabolic impairment, cardiovascular problems and diminished psychological well-being. Recent growth in wind farm developments has been associated with community complaints regarding sleep disturbance, annoyance and a range of health issues that some attribute to wind farms. Wind turbines create aerodynamic and mechanical noise that, if sufficiently loud, has the potential to disturb residents’ sleep, particularly for those living in close proximity. According to the World Health Organisation (WHO), noise effects on sleep are expected to occur with outside noise levels > 40 dB (A). On the other hand, the WHO guidelines also state that “when prominent low-frequency components are present, measures based on A-weighting are inappropriate”, so uncertainty remains regarding which alternative noise measures and noise limits are most appropriate to mitigate community impacts of wind farm noise on sleep. In Australia, dwellings are typically located > 1 km from the nearest wind turbine where wind farm noise becomes more biased towards lower frequencies (\(\le \) 200 Hz) at low sound pressure levels (\(<\sim \) 40 dB (A) outside) that may or may not be audible inside a dwelling. Nevertheless, as with any environmental noise, wind farm noise has the potential to disturb sleep, via frequent physiological activation responses and arousals affecting the micro-structure of sleep, and the overall macro-structure of sleep, including total sleep time potentially reduced by difficulty falling asleep and returning to sleep following awakenings for whatever reason. Over time, chronic insomnia could potentially develop in individuals with greater sensory acuity and/or those prone to annoyance from environmental noise. However, it is unclear if and how much sleep is disturbed by the relatively low sound pressure levels relevant to wind turbine noise. Good empirical evidence to investigate these plausible mechanisms is sparse. In this paper, we describe the psychophysiological mechanisms that underlie sleep disturbance in response to noise, review current evidence regarding the effects of wind farm noise on sleep, evaluate the quality of existing evidence and identify evolving research in this area.